The generic term Parathormone or parathyroid hormones (commonly indicated by the initials PTH eventually followed by the number of amino acids characterizing the particular fragment) refers to a series of proteins or their fragments which can be found in nature and are assigned to different physiological effects.
Such effects relate principally to the regulation of calcemic homeostasis, favouring the intestinal calcium absorption by the indirect mechanism of hydroxylation of Vitamin D, increasing the re-absorption of calcium in the renal tubules and activating the osteoclasts. More recently it was shown that PTH and PTHrP have a relaxing action on the gastrointestinal muscles and on vascular tissue. Moreover, an increase of hematic flow in the coronaries and a positive chronotropic effect and negative inotropic effect have been demonstrated.
The hormone and its fragments are dosed biologically and the measurement system presently most often used is the USP unit defined as one hundredth of the amount of parathyroid hormone required to increase the calcium contained in 100 ml of normal dog serum by 1 mg within 16-18 hours from administration.
Some studies reported in the literature indicate an in vitro action of parathormone, its fragments and the correlated peptide (PTHrP) on the contractility of rat uterus. According to such studies PTH has an inhibitory action on the contractility of the uterus induced by oxytocin, acetylcholine and prostaglandin.
Literature does not report studies evaluating the action of PTH, its fragments or PTHrP on the contractility of human myometrium, Furthermore, the data reported above cannot suggest results obtainable on the human uterus because the structural and physiological differences between these two tissues do not allow any predictability.
The rat uterus is formed of fiber cells which are completely different from those of the human myometrium. It was, therefore, not possible, according to such studies, to foresee the possibility of using such products in the prevention of abortion and premature birth in humans, since the data obtained in animals cannot be extrapolated to humans. In fact, the smooth muscles (including the human myometrium) do not normally possess fast Na+ channels, while the existence of such channels has been demonstrated in the rat uterus. Sperelakis N. et al., "Fast Na+ channels in smooth muscle from pregnant rat uterus," Can. J. Physiol. Pharmacol. (70) 491-500 (1992). Furthermore, although the concentration of receptors for oxytocin on myometrium membranes is quantitatively similar in human and guinea pig uterus, it was approximately twice that found in rat. Fuchs A. R. et al., "Oxytocin antagonist and oxytocin receptors in myometrium and decidua," Am. J. Perinatol. (6), 205-208 (1989). Moreover, Lopez Bernal A. et al. have confirmed that oxytocin does not contract the nonpregnant human uterus but contracts the non-pregnant rat uterus. Lopez Bernal A. et al., "Are leukotrienes involved in human uterine contractility?" Br. J. Obstet. Gynaecol. (96) 568-573 (1989).
We must also consider the remarkable structural differences of the two organs involved. In fact, the response of a sample of rat uterus is mostly due to the activity of longitudinal muscles while the response of human myometrium strips results from different muscular components. In addition, the behaviour of the two myometriums with respect to histamine is well known. The rat uterus in estrus responds to histamine with an inhibition which is connected to the activation of H2 receptors. Black J. W. et al., "Definition and Antagonism of histamine H2-receptors," Nature (236), 385-390 (1972). The human uterus always reacts with a contraction due to the activation of H1 receptors. Cruz M. et al., "Effects of histamine and serotonin on the contractility of isolated pregnant and nonpregnant human myometrium," Gynecol. Obstet. Invest. (28), 1-4 (1989).
Furthermore, G. Ballejo et al. have demonstrated that the response of the myometrium can depend on the animal species since the sensitivity to calcium in human uterus and in nonpregnant dog uterus did not result to be different, while in the nonpregnant rat myometrium the potency of CaCl.sub.2 in inducing contractions in a solution rich of K.sup.+ and Ca.sup.2+ was about 30-40 times higher than that shown in their studies on human myometrium. G. Ballejo et al., "In vitro effects of calcium entry blockers, chlorpromazine and fenoterol upon human pregnant myometrium contractility," Br. J. Pharmacol. (89), 515-523 (1986); Calixto J. B. e Antonio A., "Effects of Compound D600 (methoxyverapamil) on drug-induced-contractions of isolated dog uterine muscle," Gen. Pharmacol. (17), 203-209 (1986);Calixto J. B. and Loch S., "Ketamine inhibition of calcium-induced contractions in depolarized uterus. A comparison with other calcium antagonists," Br. J. Pharmacol. (85). 189-195 (1985). In conclusion, therefore, the effects observed on the human uterus cannot be extrapolated from those obtained on the rat uterus but, rather, the effect noted in vitro on human uterus is surprising.